This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alterations in the heart that occur during the aging process result in decreased myocardial function and render it more susceptible to damage. A common cause of damage to the myocardium is ischemic injury. Until now, experimental evidence linking a decline in ischemic stress tolerance to alterations in specific stress signaling pathways has been lacking. Recently, we have found that the macrophage migration inhibitory factor (MIF)-AMP-activated protein kinase (AMPK) signaling pathway plays an important role in limiting cardiac damage and dysfunction induced by ischemia/reperfusion, and aging-associated reduction in AMPK activity that may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with aging in skeletal muscles. We hypothesize that aging is associated with a decline in the ability of cardiac cells to activate this host response (MIF-AMPK cascades) to acute ischemic injury, which contributes to a reduced tolerance to ischemic insults. These experiments will examine whether normalization of AMPK activation by MIF in the aged heart mitigates injury during ischemia/reperfusion. We outline future experiments to examine the effect of modulating behaviors, namely caloric intake and exercise, on the MIF-AMPK signaling pathway in the aged heart, to elucidate the potential role of interventions that might lead to AMPK stimulation in managing cardiovascular disease in the elderly. Better understanding of the mechanisms leading to altered cardiac AMPK activation in response to ischemic stress with aging is important to fully understand the basis for increased susceptibility of the elderly to ischemic injury and could lead to therapeutic strategies aimed at limiting cardiac damage.